title: In vitro interactions between sitamaquine and amphotericin B, sodium stibogluconate, miltefosine, paromomycin and pentamidine against Leishmania donovani.
abstract: OBJECTIVE
  To evaluate in vitro interactions between sitamaquine and the current antileishmanial drugs amphotericin B, sodium stibogluconate, miltefosine, paromomycin and pentamidine against intracellular Leishmania donovani amastigotes in peritoneal mouse macrophages. A second objective was to evaluate the susceptibility of antimony-resistant L. donovani isolates to sitamaquine.
  
  
  METHODS
  Mouse peritoneal macrophages were infected with L. donovani amastigotes. Drug susceptibility was assessed in a standard 5 day assay and drug interactions with a modified fixed ratio isobologram method. Fractional inhibitory concentrations (FICs), sum FICs (∑FICs) and an overall mean ∑FIC were calculated for each combination. The nature of interaction was classified on the basis of the mean ∑FIC as follows: synergy as mean ∑FIC≤0.5, indifference as mean ∑FIC between >0.5 and ≤4 and antagonism as mean ∑FIC>4.
  
  
  RESULTS
  Interactions between sitamaquine and amphotericin B, sodium stibogluconate, paromomycin and miltefosine were classified as indifferent at the 50% and 90% effective concentration (EC50 and EC90, respectively) levels. The sitamaquine/pentamidine combination was synergistic, with overall mean ∑FICs from 0.5 to 0.6 at the EC50 level and from 0.3 to 0.7 at the EC90 level. Sitamaquine displayed in vitro activity against L. donovani isolates resistant to sodium stibogluconate.
  
  
  CONCLUSIONS
  This study expands the preclinical data on drug combinations and provides the basis for further studies as antileishmanial chemotherapy is moving towards multidrug treatment regimens.
authors.affiliation: London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK. karin.seifert@lshtm.ac.uk
authors.forename: Karin
authors.initials: K
authors.lastname: Seifert
authors.forename: Jane
authors.initials: J
authors.lastname: Munday
authors.forename: Tahmina
authors.initials: T
authors.lastname: Syeda
authors.forename: Simon L
authors.initials: SL
authors.lastname: Croft
mesh_terms: D000818:Animals; D000965:Antimony / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D006224:Cricetinae; D004347:Drug Interactions; D004351:Drug Resistance; D007893:Leishmania donovani / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000469:parasitology; D051379:Mice
chemical_list: D000981:Antiprotozoal Agents; D000965:Antimony